Sulfur mustard (SM) is a highly toxic blister agent which has been used many times in several wars and conflicts and caused heavy casualties. Ease of production and lack of effective therapies make SM a potential threat to public health. SM intoxication causes severe damage on various target organs, such as the skin, eyes, and lungs. In addition, SM exposure can also lead to hepatotoxicity and severe liver injuries. However, despite decades of research, the molecular mechanism underlying SM-induced liver damage remains obscure. SM can be converted into various products via complex hepatic metabolism in vivo. There are some pieces of evidence that one of the oxidation products of SM, divinyl sulfone (DVS), exhibits even more significant toxicity than SM. Nevertheless, the molecular toxicology of DVS is still hardly known. In the present study, we confirmed that DVS is even more toxic than SM in the human hepatocellular carcinoma cell line HepG2. Further mechanistic study revealed that DVS exposure (200 μM) promotes pyroptosis in HepG2 cells, while SM (400 μM) mainly induces apoptosis. DVS induces gasdermin D (GSDMD) mediated pyroptosis, which is independent of caspases activation but depends on the large amounts of reactive oxygen species (ROS) and severe oxidative stress produced during DVS exposure. Our findings may provide novel insights for understanding the mechanism of SM poisoning and may be helpful to discover promising therapeutic strategies for SM intoxication.

硫芥子气 （SM） 是一种剧毒泡罩剂，在多次战争和冲突中被多次使用，造成重大伤亡。易于生产和缺乏有效疗法使 SM 对公共卫生构成潜在威胁。SM 中毒会对各种靶器官造成严重损害，例如皮肤、眼睛和肺。此外，SM 暴露还会导致肝毒性和严重的肝损伤。然而，尽管进行了数十年的研究，SM 诱导的肝损伤的分子机制仍然不清楚。SM 可以通过体内复杂的肝脏代谢转化为各种产物。有一些证据表明，SM 的氧化产物之一二乙烯砜 （DVS） 表现出比 SM 更显着的毒性。然而，DVS 的分子毒理学仍然鲜为人知。在本研究中，我们证实 DVS 在人肝细胞癌细胞系 HepG2 中的毒性甚至比 SM 更大。进一步的机制研究显示，DVS 暴露 （200 μM） 促进 HepG2 细胞焦亡，而 SM （400 μM） 主要诱导细胞凋亡。DVS 诱导 gasdermin D （GSDMD） 介导的焦亡，这与 caspase 激活无关，但取决于 DVS 暴露期间产生的大量活性氧 （ROS） 和严重的氧化应激。我们的研究结果可能为理解 SM 中毒的机制提供新的见解，并可能有助于发现有前途的 SM 中毒治疗策略。